Aktiivsete ühendite disain neurodegeneratiivsete haiguste raviks

Väitekirja elektrooniline versioon ei sisalda publikatsiooneNeurodegeneratiivsed haigused on tänapäeval kujunenud keskseks meditsiiniliseks ja sotsiaalseks probleemiks. Ühest küljest on selle põhjuseks haigustega kaasnevad rasked füüsilised ja vaimsed puuded ning mõjusate ravimeetodite puudumine. Teisalt on valdav enamus neurodegeneratiivseid haigusi seotud vananemisega. Oodatava eluea märkimisväärne pikenemine on põhjustanud patsientide arvu olulist kasvu. Üks peamisi takistusi neurodegeneratiivsete häirete jaoks radikaalsete ravimeetodite leidmisel on uute ravimite väljatöötamise protsessi pikkus ja kulukus. Viimase kümnendi jooksul on aga molekulaarse modelleerimise ja tehisintellekti arvutusmeetodite kaasamine võimaldanud märkimisväärselt lühendada nii uute ravimite väljatöötamiseks kuluvat aega kui ka maksumust. Käesolevas väitekirjas rakendati mitmesuguseid arvutipõhiseid ravimite otsimise meetodeid uute potentsiaalsete aktiivsete keemiliste ühendite väljatöötamiseks neurodegeneratiivsete haiguste raviks. Kaasaegsete arvutikeemia molekulaarsildamise ja molekulaardünaamika meetodite abil sõeluti virtuaalselt suuri keemiliste ühendite andmebaase, leidmaks neurodegeneratiivsete haigustega seotud valkudele toimivaid aineid. Nii tehti kindlaks rida uusi looduslikke ühendeid, mis toimivad erinevate ensüümvalkude inhibiitoritena, aga ka uudne ühend, mis toimib efektiivselt samaaegselt kahele Alzheimeri tõvega seotud valgule. Üks peamisi neurodegeneratiivsete haiguste tekke põhjusi on nn närvikasvufaktorite puudulikkus neuronites. Seetõttu on väga huvitavaks ja perspektiivseks suunaks keemiliste ühendite leidmine, mis käituksid analoogselt nende faktoritega ning kaitseks närvirakke suremise eest. Käesoleva töö käigus uuriti erinevate arvutusmeetodite abil põhjalikult ühe taolise närvikasvufaktori (gliia närvikasvufaktor GDNF) toimemehhanismi ning ennustati seda faktorit imiteeriv aktiivne ühend. Kuigi selle eksperimentaalselt mõõdetud neuroneid kaitsev toime ei vasta veel ravimitele esitatavatele nõutele, on siiski tegemist esimese sellelaadse ühendiga maailmas, mille alusel oleks võimalik välja arendada täiesti uut tüüpi ravimeid nii Parkinsoni kui ka Huntingtoni tõve raviksToday, neurodegenerative diseases are one of the most acute medical and social problems. This is due to both severe physical and mental disabilities resulting from the constant progression of the process, and the age-dependent nature of the vast majority of neurodegenerative diseases. The current accelerating increase in life expectancy inevitably leads to a significant increase in the number of such patients. There is currently no radical treatment for neurodegenerative disorders. One of the main obstacles to finding effective drugs is the length and cost of the process of developing a new drug. However, the development of modern molecular modelling and artificial intelligence methods has substantially shortened the time to dispense new medicines and reduced their cost. This dissertation provides examples of the use of various methods of computer-aided drug design such as molecular docking and molecular dynamics to develop new potential candidates against neurodegenerative diseases. The high-throughput virtual screening of large molecular libraries enabled to identify effective compounds against target proteins related to neurodegenerative diseases. In result, a series of natural compounds acting as inhibitors to enzymes related to different diseases was established. Notably, a fully novel compound acting against two proteins related to Alzheimer’s disease was predicted and experimentally verified. One of the main causes of the neurodegeneration is the mostly age-related deficiency of so called neurotrophic factors. Small molecules that can mimic the activity of these factors in cells would be thus very attractive novel drug candidates. In the present thesis, the computational modelling was used for detailed study of the mechanism of action of one of the most important neurotrophic factors (glial cell-derived neurotrophic factor GDNF). The results of this study enabled to develop first time a compound that acted similarly to this factor itself. Whereas the experimentally measured activity of this compound was moderate, it creates a basis for the development of fully new type of drugs against Parkinson’s and Huntington’s diseases.https://www.ester.ee/record=b535990

Phonosemantic interpretation of lexical units in the context of Russian and Slovak linguocultures

Phonosemantics is one of the youngest disciplines in the modern linguistics but takes an important part in the intercultural communication. The purpose of the article is to carry out the comparative analysis of lexical units of the Russian and Slovak language systems from the perspective of phonosemantics and philological hermeneutics. There has been made an attempt to study the correlation between the phonetic and semantic motivations of lexemes and paroemias (proverbs and sayings) in the system of the Russian and Slovak languages ​​on the basis of the phonosemantic analysis and hermeneutic method. The mechanism for determining the language ​​ connotation on the knowledge based system makes it possible to reveal the linguocultural peculiarities of phraseological units, taking into account national-cultural, territorial, ethnolinguistic factors provided the individual’s cognitive abilities are activated. The problem of decoding of semantics in the situation of cross-cultural cooperation is not researched only from the view of the traditional linguistics, but also by means of cognitive activities: perception, presentation, reflection, interpretation. The adequate interpretation of the linguo-cultural phenomena and lexical units is the reflection in the internal communication  aimed at the decoding of cultural and language code. In the external communication the reflection of the individual is expressed in the  interpretation. The phonosemantic analysis, based on the description of natural-cultural lexical blocks from the view of philological hermeneutics, was revealed at first differences and similarities in Russian and Slovak languages; secondly, it were determined the so-called linguocultural codes. The analysis of lexical units in the Russian and Slovak languages has revealed common and distinctive peculiarities of the languages regarding their phonology and semantics. Perception and interpretation of linguistic units in foreign culture helps to achieve the most important communicative and pragmatic purpose – the establishment of intercultural and interpersonal parity and mutual understanding in the process of communicative interaction

Mokslo populiarinimo tekstų vertimo analizė remiantis relevantiškumo teorija

In the present paper, the authors analyze a translation process implemented within the framework of Relevance Theory using Adaptation Theory as a tool to ensure relevance in the translation of popular science texts. The paper is part of ongoing research dedicated to the development of methodology for translation of popular science texts on architecture, ICT, and economics, focused here on translating from English into Latvian. Recognizing that relevance in translation is a qualitative category, the authors suggest measuring it along two dimensions: the plane of content and the plane of expression. Having defined four categories of relevance, the authors have developed a grid that may be recommended as a guide in a translator’s decision-making process for selecting a particular adaptive strategy and translation method.Šiame straipsnyje vertimo procesas analizuojamas taikant relevantiškumo teorijos sistemą. Pasinaudodamos adaptacijos teorija kaip priemone užtikrinti relevantiškumą verčiant mokslo populiarinimo tekstus, straipsnio autorės kuria šių tekstų vertimo iš anglų kalbos į latvių kalbą metodiką. Straipsnyje pristatoma medžiaga yra šiuo metu vykdomo platesnio architektūros, IKT ir ekonomikos sričių mokslo populiarinimo tekstų vertimo tyrimo dalis. Laikomasi nuomonės, kad relevantiškumas vertime yra pamatuojama kategorija – autorės siūlo jį vertinti dviem pjūviais: pagal relevantiškumo laipsnį ir pagal relevantiškumo lygį, t. y. turinio ir raiškos lygmeniu. Tuo remdamosi autorės sukūrė tinklelį, kurį rekomenduoja taikyti vertėjui priimant sprendimus, kai reikia pasirinkti tam tikrą procedūrą ar vertimo būdą

Creation and Extension of Meaning in Professional Communication

The application of different language resources in professional communication reveals the role of cognition in information processing, the interpretive function of language in knowledge construction, and the interrelation of linguistic and extra-linguistic environments. The aim of the present paper is to examine the development of the language of science and the way it is influenced by history, technology, media, genre, and culture. Integrating cognitive approach and pragmatic analysis, the ways of meaning creation and meaning extension have been studied in the popular science texts. Creative thinking and imagination are considered responsible for innovative, creative and insightful thought in general, and, sometimes, for a much wider range of mental activities

Innovations in Human Stem Cell Research: A Holy Grail for Regenerative Medicine

Stem cells are unspecialized cells capable of renewing themselves and giving rise to differentiated and specialized cell subtypes. There are two general categories of stem cells, i.e., pluripotent stem cells capable of differentiation into any cell type in the human body and multipotent adult stem cells maintaining tissue homeostasis in postnatal life. Investigations in both these categories of stem cells have expanded our knowledge on human organogenesis and tissue regeneration and have suggested potential therapeutic functions of stem cells in regenerative medicine. The advent of induced pluripotent stem cell (iPSC) technology a decade ago further revolutionized stem cell biology and has given rise to the translation of stem cell-based therapies. This chapter will summarize some of the exciting progress and challenges in the applications of iPSC-derived stem cells and adult stem cells and the potential of translational and clinical research of these stem cells in regenerative medicine

МИХАИЛ МИХАЙЛОВИЧ ОДИНЦОВ В МУЗЕЙНОЙ ЭКСПОЗИЦИИ ИНСТИТУТА ЗЕМНОЙ КОРЫ

The Museum of the Institute of the Earth’s Crust opened an exhibition devoted to Mikhail M. Odintsov (1911–1980), the prominent Russian geologist and the corresponding member of the USSR Academy of Sciences, who headed the Institute of the Earth’s Crust from 1954 to 1976. He was among researchers who pioneered in discovering diamonds in Siberia, Russia. He determined promising diamondbearing areas in Yakutia. The kimberlitic nature wad established, and the diamondiferous kimberlite prospecting method was developed. Prospective diamondbearing capacities were forecasted for the southern part of the Siberian platform and the Prisayanie. The Angara-Vilui ore belt was defined as the largest mineragenic sub-province in the southern East Siberia. The exhibition was opened on 07 November 2011 when the All-Russia Conference devoted to the 100th anniversary of Mikhail M. Odintsov took place in Irkutsk. It presents photographs, personal belongings and documents that provide information about Mikhail M. Odintsov’s childhood and youth years, pedagogical activities, field studies, researches, multidiscipline scientific organization, social and political activities. A collection of kimberlite samples from Yakutia and beyond supports the exposition. A model of the Mir kimberlite pipe is presented; it is the first diamondiferous kimberlite found in June 1955 and developed in Siberia.В Музее ИЗК СО РАН открыта экспозиция, посвященная жизни и деятельности выдающегося сибирского геолога, директора ИЗК с 1954 г. по 1976 г., члена-корреспондента Академии наук СССР, профессора Михаила Михайловича Одинцова. Михаил Михайлович Одинцов – один из первооткрывателей сибирских алмазов. Им выделены территории Якутии, перспективные на обнаружение источников алмазов. Установлена их кимберлитовая природа, и разработана методика поисков алмазоносных кимберлитов. Намечены перспективы алмазоносности юга Сибирской платформы и Присаянья. Выделен Ангаро-Вилюйский рудный пояс – крупнейшая минерагеническая субпровинция юга Восточной Сибири. Открытие выставки состоялось 7 ноября 2011 г. в рамках Всероссийской конференции, посвященной 100-летию со дня рождения М.М. Одинцова. Экспозиция размещена в малом конференц-зале института и представлена демонстрационными фотостендами, личными вещами и документами, повествующими о детских и юношеских годах, о педагогической деятельности, о полевых работах геологапоисковика и научных изысканиях, о многогранной научноорганизационной и общественно-политической деятельности М.М. Одинцова. Экспозиция развёрнута на фоне коллекции кимберлитов Якутии и других регионов мира. Демонстрируется макет кимберлитовой трубки Мир, открытой в июне 1955 г., – первого разрабатываемого месторождения алмазов в нашей стране

Kazimir Malevich’s Studio in the Second State Free Art Studios (Moscow, 1918–1919)

This study publishes the results yielded when examining archival materials (RGALI archive and MArhI Museum) containing authentic students (apprentices) lists of the Free State Art Studios. These unique artistic institutions were founded in 1918 in Moscow following the avant-garde reform of specialised education. This article publishes three interconnected lists of Moscow students (apprentices) of K. S. Malevich in the Second Free State Art Studios. The authors compare the lists with each other. With reference to them, the article examines the history of the formation of the “individual” workshop of the outstanding avant-garde artist. The pedagogical activity was an integral part of Malevich’s artistic biography, but so far only the relatively late stages of his teaching in Vitebsk and Petrograd (Leningrad) have been studied. The short but eventful Moscow stage (November 1918 — October 1919), which saw the formation of the principles of Malevich’s pedagogy, has not been studied previously yet. The authors comment on the main events of the two training seasons of the life of the “individual” workshop until the Headmaster’s departure to Vitebsk (October 1919). Additionally, the authors describe the personalities of the Moscow apprentices, illustrating the events behind their appearance in Malevich’s orbit. The article contains data on the artistic biographies of painters, sculptors, architects, and designers who are famous nowadays, i.e. I. Zavyalov, G. Klutsis, Z. Komissarenko, G. Krutikov, I. Kudryashov, I. Meerzon, A.-Ya. Minchin, T. Shapiro, etc. Also, nearly forgotten authors grouped around Malevich too, and to a considerable extent, they determined the general cultural background of avant-garde art. The data published help expand the idea about Malevich’s school and the originality of his workshop in Moscow, explaining the specific forms and context of the interaction among artists. Many of Malevich’s Moscow apprentices themselves became organisers of Free State Art Studios in the regions